Cyclohexyl amine derivatives and their use as tachykinin antagonists

ABSTRACT

Compounds of formula (I), and salts and prodrugs thereof wherein X, R 2 , R 3 , R 4 , R 5 , R 7  and R 8  are defined herein, are tachykinin receptor antagonists. ##STR1##

This invention relates to a class of cyclic compounds, which are usefulas tachykinin antagonists. More particularly, the compounds of theinvention comprise a cyclohexyl ring system substituted by anarylmethyloxy or arylmethylthio moiety, phenyl and an optionallysubstituted amino group.

The tachykinins are a group of naturally-occurring peptides found widelydistributed throughout mammalian tissues, both within the centralnervous system and in the peripheral nervous and circulatory systems.The three known mammalian tachykinins are: substance P, neurokinin A andneurokinin B:

Evidence for the usefulness of tachykinin receptor antagonists in pain,headache, especially migraine, Alzheimer's disease, multiple sclerosis,attenuation of morphine withdrawal, cardivascular changes, oedema, suchas oedema caused by thermal injury, chronic inflammatory diseases suchas rheumatoid arthritis, asthma/bronchial hyperreactivity and otherrespiratory diseases including allergic rhinitus, inflammatory diseasesof the gut including ulcerative colitis and Crohn disease, ocular injuryand ocular inflammatory diseases, proliferative vitreoretinopathy,irritable bowel syndrome and disorders of bladder function includingcystitis and bladder detruser hyper-reflexia is reviewed in "TachykininReceptors and Tachykinin Receptor Antagonists", C. A. Maggi, R.Patacchini, P. Rovero and A. Giachetti, J. Auton. Pharmacol. (1993) 13,23-93. Tachykinin antagonists are also believed to be useful in allergicconditions [Hamelet et al Can. J. Pharmacol. Physiol. (1988) 66 1361-7],immunoregulation [Lotz et al Science (1988) 241 1218-21 and Kimball etal, J. Immunol. (1988) 141 (10) 3564-9], and as anticonvulsants [Garantet al., Brain Research (1986) 382 372-8]. Tachykinin antagonists mayalso be useful in the treatment of small cell carcinomas, in particularsmall cell lung cancer (SCLC) [Langdon et al., Cancer Research (1992)52, 4554-7].

It has furthermore been suggested that tachykinins have utility in thefollowing disorders: depression, dysthymic disorders, chronicobstructive airways disease, hypersensitivity disorders such as poisonivy, vasospastic diseases such as angina and Reynauld's disease,fibrosing and collagen diseases such as scleroderma and eosinophillicfascioliasis, reflex sympathetic dystrophy such as shoulder/handsyndrome, addiction disorders such as alcoholism, stress related somaticdisorders, neuropathy, neuralgia, disorders related to immuneenhancement or suppression such as systemic lupus erythmatosis (Europeanpatent application no. 0 436 334), conjuctivitis, vernal conjunctivitis,contact dermatitis, atropic dermatitis, urticaria, and other eczematoiddermatitis (European patent application no. 0 394 989) and emesis(European patent application no. 0 533 280).

We have now found a class of non-peptides which are potent antagonistsof tachykinin.

European patent application no. 0 436 334 discloses 4- to 7-memberedazacyclic compounds substituted at the 3-position by a benzylsubstituted amino moiety and at the 2-position by an aryl moiety. Thecompounds are said to be tachykinin antagonists.

The present invention provides a compound of formula (I), or a salt orprodrug thereof: ##STR2## wherein X represents O or S;

R¹ represents phenyl optionally substituted by 1, 2 or 3 groups selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, cyano, nitro,trifluoromethyl, trimethylsilyl, --OR^(a), SR^(a), SOR^(a), SO₂ R^(a),--NR^(a) R^(b), --NR^(a) COR^(b), --NR^(a) CO₂ R^(b), --CO₂ R^(a) or--CONR^(a) R^(b) ;

R² represents phenyl optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy,halo or trifluoromethyl;

R³ and R⁴ each independently represent H, COR^(a), CO₂ R^(a) or C₁₋₆alkyl optionally substituted by a group selected from (CO₂ R^(a),CONR^(a) R^(b), hydroxy, cyano, COR^(a), NR^(a) R^(b), and phenyloptionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, halo ortrifluoromethyl);

R⁵ represents H or XCH₂ R⁶ wherein R⁶ represents phenyl optionallysubstituted by 1, 2 or 3 groups selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl,--OR^(a), SR^(a), SOR^(a), SO₂ R^(a), --NR^(a) R^(b), --NR^(a) COR^(b),--NR^(a) CO₂ R^(b), --CO₂ R^(a) or --CONR^(a) R^(b) and X is aspreviously defined;

R⁷ and R⁸ each independently represent H or C₁₋₆ alkyl; and

R^(a) and R^(b) each independently represent H, C₁₋₆ alkyl, phenyl ortrifluoromethyl.

As used herein, the definition of each expression, when it occurs morethan once in any structure, is intended to be independent of itsdefinition elsewhere in the same structure.

The alkyl, alkenyl and alkynyl groups referred to with respect to theabove formula may represent straight, branched or cyclic groups orcombinations thereof. Thus, for example, suitable alkyl groups includemethyl, ethyl, n- or iso-propyl, n-, sec-, iso- or tert-butyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and cycloalkyl-alkylgroups such as cyclopropylmethyl; suitable alkenyl groups include vinyland allyl; and suitable alkynyl groups include propargyl.

The term "halo" as used herein includes fluoro, chloro, bromo and iodo,especially chloro and fluoro.

A subgroup of compounds according to the invention is represented bycompounds of formula (I) wherein R⁷ and R⁸ each represent H, and saltsand prodrugs thereof.

Preferably X represents O.

Preferably R¹ represents substituted phenyl. When R¹ is substitutedphenyl suitable substituents include C₁₋₆ alkyl, nitro, trifluoromethyl,trimethylsilyl, bromo, chloro, fluoro, iodo, cyano, methyl, ethyl,cyclopropyl, vinyl, methoxy, phenoxy, amino and carbonylmethoxy.Preferably R¹ represents phenyl substituted by one or more groupsselected from methyl and trifluoromethyl. More preferably R¹ representsdisubstituted phenyl, especially 3,5-dimethylphenyl or3,5-bis(trifluoromethyl)phenyl.

Preferably R² represents unsubstituted phenyl.

Suitable values for R³ and R⁴ include H, C₁₋₆ alkyl, such as methyl, andsubstituted C₁₋₆ alkyl, such as C₁₋₆ alkyl, preferably CH₁₋₄ alkyl, morepreferably CH₂, substituted by CONR¹⁰ R¹¹, especially CONH₂, or CO₂R^(a), such as CO₂ CH₃.

Preferably at least one of R³ and R⁴ represents H. More preferably oneof R³ and R⁴ represents H and the other of R³ and R⁴ represents H or CH₂CONH₂.

Preferably R⁵ represents H.

For use in medicine, the salts of the compounds of formula (I) will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds according to the invention (such asthe dibenzoyltartrate salts) or of their pharmaceutically acceptablesalts. Suitable pharmaceutically acceptable salts of the compounds ofthis invention include acid addition salts which may, for example, beformed by mixing a solution of the compound according to the inventionwith a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulphuric acid, oxalic acid, fumaric acid, maleicacid, succinic acid, acetic acid, citric acid, tartaric acid, carbonicacid, phosphoric acid or p-toluenesulphonic acid. Salts of amine groupsmay also comprise quaternary ammonium salts in which the amino nitrogenatom carries a suitable organic group such as an alkyl, alkenyl, alkynylor aralkyl moiety. Furthermore, where the compounds of the inventioncarry an acidic moiety, suitable pharmaceutically acceptable saltsthereof may include metal salts such as alkali metal salts, e.g. sodiumor potassium salts; and alkaline earth metal salts, e.g. calcium ormagnesium salts.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs",ed. H. Bundgaard, Elsevier, 1985.

The compounds according to the invention may exist both as enantiomersand as diastereomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention.

A particular sub-class of compounds according to the invention isrepresented by compounds of formula (Ia), and salts and prodrugsthereof: ##STR3## wherein R², R³ and R⁴ are as defined for formula (I);and

R²⁰ and R²¹ independently represent H C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, OR^(a),SR^(a) SOR^(a), SO₂ R^(a), NR^(a) R^(b), NR^(a) COR^(b), NR^(a) CO₂R^(b), COR^(a) or CONR^(a) R^(b), where R^(a) and R^(b) are aspreviously defined.

Preferably R²⁰ and R²¹ are selected from H, C₁₋₆ alkyl, such as t-butyl,ethyl or methyl, C₁₋₆ alkoxy, such as methoxy, halo, such as chloro,bromo or iodo, and trifluoromethyl.

The substance P antagonizing activity of the compounds described hereinwas evaluated using the human NK1R assay described in published Europeanpatent application no. 0 528 495. The method essentially involvesdetermining the concentration of the test compound required to reduce by50% the amount of radiolabelled substance P binding to human NK1R,thereby affording an IC₅₀ value for the test compound. The compounds ofExamples 1, 5 and 6 were found to have IC₅₀ values of 100 nM, 350 nM and100 nM, respectively.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, solutions or suspensions, or suppositories, for oral,parenteral or rectal administration, or topical administration includingadministration by inhalation or insufflation.

The invention further provides a process for the preparation of apharmaceutical composition comprising a compound of formula (I), or asalt or prodrug thereof, and a pharmaceutically acceptable carrier,which process comprises bringing a compound of formula (I), or a salt orprodrug thereof into association with a pharmaceutically acceptablecarrier.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are adminsitered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably sterile pharmaceutically acceptable solvents may be nebulisedby use of inert gases. Nebulised solutions may be breathed directly fromthe nebulising device or the nebulising device may be attached to a facemask, tent or intermittent positive pressure breathing machine.Solution, suspension or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

For topical administration, for example as a cream, ointment or lotion,pharmaceutically acceptable carriers are, for example, water, mixturesof water and water-miscible solvents such as lower alkanols orarylalkanols, vegetable oils, polyalkylene glycols, petroleum basedjelly, ethyl cellulose, ethyl oleate, carboxymethylcellulose,polyvinylpyrrolidone, isopropyl myristate and otherconventionally-employed non-toxic, pharmaceutically acceptable organicand inorganic carriers. The pharmaceutical preparation may also containnon-toxic auxiliary substances such as emulsifying, preserving, wettingagents, bodying agents and the like, as for example, polyethyleneglycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and10,000, antibacterial components such as quaternary ammonium compounds,phenylmercuric salts known to have cold sterilizing properties and whichare non-injurious in use, thimerosal, methyl and propyl paraben, benzylalcohol, phenyl ethanol, buffering ingredients such as sodium chloride,sodium borate, sodium acetates, gluconate buffers, and otherconventional ingredients such as sorbitan monolaurate, triethanolamine,oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodiumsulfosuccinate, monothioglycerol, thiosorbitol, ethylenediaminetetraacetic acid, and the like.

The compounds of formula (I) are of value in the treatment of a widevariety of clinical conditions which are characterized by the presenceof an excess of tachykinin, in particular substance P, activity. Thesemay include disorders of the central nervous system such as anxiety,depression, psychosis and schizophrenia; epilepsy; neurodegenerativedisorders such as dementia, including senile dementia of the Alzheimertype, Alzheimer's disease and Down's syndrome; demyelinating diseasessuch as multiple sclerosis (MS) and amyotropic lateral sclerosis (ALS;Lou Gehrig's disease) and other neuropathological disorders such asperipheral neuropathy, for example, diabetic or chemotherapy-inducedneuropathy, and postherpetic and other neuralgias; small cell carcinomasuch as small cell lung cancer; respiratory diseases such as chronicobstructive airways disease, bronchopneumonia, bronchospasm and asthma;inflammatory diseases such as inflammatory bowel disease, irritablebowel syndrome, psoriasis, fibrositis, osteoarthritis and rheumatoidarthritis; allergies such as eczema and rhinitis; hypersensitivitydisorders such as poison ivy; ophthalmic diseases such asconjunctivitis, vernal conjunctivitis, and the like, and proliferativevitreoretinopathy; cutaneous diseases such as contact dermatitis,atropic dermatitis, urticaria, and other eczematoid dermatitis; oedema,such as oedema caused by thermal injury; addiction disorders such asalcoholism; stress related somatic disorders; reflex sympatheticdystrophy such as shoulder/hand syndrome; dysthymic disorders; adverseimmunological reactions such as rejection of transplanted tissues anddisorders related to immune enhancement or suppression such as systemiclupus erythematosis; gastrointestinal (GI) disorders and diseases of theGI tract such as disorders associated with the neuronal control ofviscera such as ulcerative colitis, Crohn's disease and incontinence;emesis, including acute, delayed and anticipatory emesis, for example,induced by chemotherapy, radiation, toxins, pregnancy, vestibulardisorders, surgery, migraine and variations in intercranial pressure;disorders of bladder function such as cystitis and bladder detrusorhyper-reflexia; fibrosing and collagen diseases such as scleroderma andeosinophilic fascioliasis; disorders of blood flow caused byvasodilation and vasospastic diseases such as angina, migraine andReynaud's disease; and pain or nociception, for example, thatattributable to or associated with any of the foregoing conditions,especially the transmission of pain in migraine.

The compounds of formula (I) are particularly useful in the treatment ofpain or nociception and/or inflammation and disorders associatedtherewith such as, for example, neuropathy, such as diabetic andchemotherapy-induced neuropathy, postherpetic and other neuralgias,asthma, osteroarthritis, rheumatoid arthritis and especially migraine.

The present invention further provides a compound of formula (I) for usein therapy.

According to a further or alternative aspect, the present inventionprovides a compound of formula (I) for use in the manufacture of amedicament for the treatment of physiological disorders associated withan excess of tachykinins, especially substance P.

The present invention also provides a method for the treatment orprevention of physiological disorders associated with an excess oftachykinins, especially substance P, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound of formula (I) or a composition comprising acompound of formula (I).

For the treatment of certain conditions it may be desirable to employ acompound according to the present invention in conjunction with anotherpharmacologically active agent. For example, for the treatment ofrespiratory diseases such as asthma, a compound of formula (I) may beused in conjunction with a bronchodilator, such as a β₂ -adrenergicreceptor antagonist or tachykinin antagonist which acts at NK-2receptors. The compound of formula (I) and the bronchodilator may beadministered to a patient simultaneously, sequentially or incombination.

The present invention accordingly provides a method for the treatment ofa respiratory disease, such as asthma, which method comprisesadministration to a patient in need thereof of an effective amount of acompound of formula (I) and an effective amount of a bronchodilator.

The present invention also provides a composition comprising a compoundof formula (I), a bronchodilator, and a pharmaceutically acceptablecarrier.

In the treatment of the conditions associated with an excess oftachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day,in particular about 0.01 to about 25 mg/kg, such as from about 0.05 toabout 10 mg/kg per day. For example, in the treatment of conditionsinvolving the neurotransmission of pain sensations, a suitable dosagelevel is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10mg/kg per day, and especially about 0.005 to 5 mg/kg per day. Thecompounds may be administered on a regimen of 1 to 4 times per day,preferably once or twice per day.

The compounds according to the invention wherein R³ and R⁴ bothrepresent H may be prepared by a process which comprises treatment of anintermediate of formula (II): ##STR4## wherein R¹, R⁵, R⁷, R⁸ and X areas defined for formula (I) and R³⁰ represents an alkyl or, preferably, aphenyl group, with a reagent of formula R² --M, where R² is as definedfor formula (I) and M represents an alkali metal, such as lithium.

The reaction is conveniently effected in a suitable organic solvent,such as an ether, for example, tetrahydrofuran.

Compounds of formula (I) where one or both of R³ and R⁴ and are otherthan H may be prepared from compounds of formula (I) wherein both of R³and R⁴ represent H by conventional procedures, for example, reactionwith a suitable alkylating or acylating agent. Suitable procedures aredescribed in the accompanying examples, and further procedures will bereadily apparent to those skilled in the art.

Intermediates of formula (II) may be prepared from compounds of formula(III): ##STR5## wherein R¹, R⁵, R⁷, R⁸ and X are as defined for formula(I), by reaction with a compound of formula R³⁰ --S--S--R³⁰ in thepresence of ammonia and a nitrite, such as, for example, silver nitrite.

Compounds of formula (III) may be prepared by oxidation of thecorresponding alcohols of formula (IV): ##STR6## wherein R¹, R⁵, R⁷, R⁸and X are as previously defined by conventional methods.

Conveniently the oxidation is effected under Swern conditions, i.e. withthe use of oxalyl chloride in the presence of dimethyl sulphoxide. Othersuitable oxidation procedures will be readily apparent to those skilledin the art.

Compounds of formula (IV) may be prepared by reaction of compounds offormula (V) with compounds of formula (VI): ##STR7## wherein R¹, R⁵, R⁷,R⁸ and X are as previously defined, in the presence of a base.

Suitable bases of use in reaction include metal hydrides, such as, forexample, potassium hydride, and alumina.

The compound of formula (V) wherein R⁵ is H is commercially available.

The compounds of formula (V) wherein R⁵ is XCH₂ R⁶ may be prepared byreaction of a compound of formula (VII) with a compound of formula(VIII): ##STR8## wherein X and R¹ are as previously defined and Lrepresents a leaving group such as halo, for example, bromo or iodo.

Compounds of formulae (VII) and VIII) are commericially available or maybe prepared from commercially available starting materials by knownprocedures.

Where the above-described process for the preparation of the compoundsaccording to the invention gives rise to mixtures of stereoisomers theseisomers may, if desired, be separated, suitably by conventionaltechniques such as preparative chromatography.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The following Examples illustrate the preparation of compounds accordingto the invention.

EXAMPLE 1 1-(3,5-Dimethylbenzyloxy)-2-amino-2-phenylcyclohexane

a) A toluene (70 ml) solution containing cyclohexene oxide (20 g),3,5-dimethylbenzyl alcohol and alumina (5 g) was heated at reflux for 16h with azeotrophic removal of water. The solution was filtered and thesolvent removed in vacuo to give1-(3,5-dimethylbenzyoxy)-2-hydroxycyclohexyl as an oil.

b) The product of Example 1a (10 g) was oxidized under standard Swernconditions (JOC, 1978, 43, 2480) using oxalyl chloride (4.12 ml) anddimethyl sulphoxide (6.7 ml). The product was purified on silica geleluting with petroleum ether-ethyl acetate mixtures to give1-(3,5-dimethylbenzyoxy)-2-cyclohexanone as an oil. ¹ H NMR (360 MHz,CDCl₃) ? δ 1.61-1.96 (6H, m), 2.16-2.27 (1H, m), 2.30 (6H, s), 2.52-2.57(1H, m), 3.85-3.90 (1H, m), 4.39, 4.68 (2H, ABq, J=11.6 Hz), 6.97 (2H,s) and 6.92 (1H, s).

c) The product of Example 1b (6.90 g) was converted into thecorresponding sulphenimine using the procedure of Davis (JOC, 1973, 38,2809) by treatment with silver nitrate (4.9 g), phenyl disulphide (6.5g) and ammonia. The crude product was purified on silica gel elutingwith petroleum ether-ethyl acetate mixtures to give1-(3,5-dimethylbenzyoxy)-2-phenyl sulphenimine cyclohexane. ¹ H NMR (360MHz, CDCl₃) δ 1.42-1.62 (2H, m), 1.68-1.76 (1H, m), 1.86-1.93 (2H, m),2.07-2.12 (1H, m), 2.30 (6H, s), 2.44-2.64 (2H, m), 4.03 (1H, t, J=3.6Hz), 4.36-4.50 (2H, ABq, J=11.7 Hz), 6.91 (1H, s), 6.96 (2H, s) and7.16-7.57 (5H, m).

d) 1-(3,5-Dimethylbenzyoxy)-2-phenylsulphenimine cyclohexane (Example1c, 5.80 g) was dissolved in ether (100 ml) at 0° C. Phenyllithium (17.1ml) was added and after 1 hour the reaction mixture was heated toreflux. The reaction was quenched with 2M-sodium hydroxide (100 ml) andthe product extracted into ethyl acetate (3×50 ml). The combined organicphase was washed with water (2×50 ml), saturated sodium chloride (50ml), dried (MgSO₄) and evaporated in vacuo. The product was purified onsilica eluting with petroleum ether-ethyl acetate mixtures to give1-(3,5-dimethylbenzyoxy)-2-amino-2-phenylcyclohexane as a crystallinesolid. mp=75°-78° C. ¹ H NMR (360 MHz, CDCl₃) δ 1.18-1.23 (2H, m),1.25-1.31 (1H, m), 1.42-1.48 (2H, m), 1.88-1.92 (1H, m), 2.03-2.10 (1H,m), 2.24 (6H, s), 2.34-2.38 (1H, m), 4.38 (1H, brs), 4.45, 4.51 (2H,ABq, J=11 Hz), 6.88 (2H, s), 6.90 (1H, s), 7.15-7.25 (3H, m) and7.47-7.49 (2H, m). Found: C, 65.88; H, 7.67; N, 3.39; C₂₁ H₂₇ NO. C₂ H₂O₄ (H₂ O) requires C, 66.16; H, 7.48; N, 3.36%.

EXAMPLE 2 1-(3,5-Dimethylbenzyloxy)-2-dimethylamino-2-phenylcyclohexane

To a solution of acetic acid (1.6 ml) formaldehyde (1.10 ml) and sodiumcyanoborohydride (0.7 g) was added1-(3,5-dimethylbenzyoxy)-2-amino-2-phenylcyclohexane (1.7 g, Example 1d)in methanol. After stirring the solution for 2 hours, ethyl acetate andwater was added and the organic phase dried (MgSO₄). Evaporation of thesolvent in vacuo and column chromatography on silica gel (eluting withpetroleum ether-ethyl acetate mixtures) gave the title compound. ¹ H NMR(360 MHz, CDCl₃) δ 1.18-1.25 (4H, m), 1.56-1.64 (2H, m), 1.99 (6H, s),2.02-2.10 (1H, m), 2.32 (6H, s), 2.37-2.49 (1H, m), 4.10-4.13 (1H, m),4.50, 4.69 (2H, ABq, J=11.8 Hz), 6.93 (1H, s), 7.07 (2H, s) and7.17-7.33 (5H, m). Found: C, 80.56; H, 9.06; N, 4.39; C₂₃ H₃₁ NO. (0.25)H₂ O requires C, 80.77; H, 9.28; N, 4.09%.

EXAMPLE 31-(3,5-Dimethylbenzyoxy)-2-methoxycarbonylmethylamino-2-phenylcyclohexane

A solution of 1-(3,5-dimethylbenzyoxy)-2-amino-2-phenylcyclohexane (0.6g, Example 1d), methylbromoacetate (0.38 ml) and triethylamine (0.54 ml)in tetrahydrofuran (30 ml) was heated to reflux for 6 hours. Afterevaporation of the solvent the residue was redissolved in ethyl acetate(50 ml) which was washed with water (50 ml), saturated sodium chloride(50 ml), dried (MgSO₄) and evaporated in vacuo. The residue was purifiedby column chromatography on silica gel eluting with petroleumether-ethyl acetate mixtures to give the title compound. ¹ H NMR (250MHz, CDCl₃) δ 1.20-1.35 (2H, m), 1.58-1.84 (4H, m), 1.88-2.0 (2H, m),2.24 (6H, s), 3.16, 3.24 (2H, ABq, J=15 Hz), 3.50 (1H, m), 3.71 (3H, s),4.08, 4.31 (2H, ABq, J=12 Hz), 6.68 (2H, s), 6.84 (1H, s) and 7.22-7.48(5H, m).

EXAMPLE 41-(3,5-Dimethylbenzyoxy)-2-(carboxamido)methylamino-2-phenylcyclohexane

Ammonia gas was bubbled through a cooled solution of1-(3,5-dimethylbenzyoxy)-2-methoxycarbonylmethylamino)-2-phenylcyclohexane (0.38 g, Example 3) in methanol (20 ml). After 16hours the solvent was removed in vacuo and the residue purified bycolumn chromatography on silica gel eluting with petroleum ether-ethylacetate mixtures to give the title compound; m/e FAB 368 (M+H). ¹ H NMR(360 MHz, CDCl₃) δ 1.37-1.40 (2H, m), 1.58-1.94 (6H, m), 2.15 (6H, s),2.78-2.83 (2H, m), 2.93-2.99 (1H, m), 3.40-3.42 (1H, m), 3.89, 4.22 (2H,ABq, J=11.8 Hz), 6.50 (2H, s), 6.79 (1H, s), 7.01 (1H, brs) and7.21-7.42 (5H, m).

The oxalate salt was recrystallized from ethanol/water. mp 72°-76° C.Found: C, 63.80; H, 7.06; N, 5.54; C₂₃ H₃₀ N₂ O₂.1.25(C₂ H₂ O₄) requiresC, 63.93; H, 6.83; N, 5.84%.

EXAMPLE 51-(Bis-3,5-trifluoromethylbenzyoxy)-2-amino-2-phenylcyclohexane

The title compound was prepared using an analogous procedure as outlinedin Example 1 but using Bis-3,5-trifluoromethylbenzyl alcohol. ¹ H NMR(360 MHz, DMSO) δ 1.40-1.52 (2H, m), 2.61-2.73 (2H, m), 2.78-2.84 (2H,m), 1.98-2.04 (1H, m), 2.06-2.09 (1H, m), 4.02 (1H, t, J=6.3 Hz), 4.50,4.79 (2H, ABq, J=12.9 Hz), 7.33-7.43 (3H, m), 7.59-7.61 (2H, m), 7.85(2H, s) and 7.96 (1H, s). The oxalate salt was recrystallized fromethanol/water mp 119°-122° C. Found: C, 53.96; H, 4.48; N, 2.70; C₂₁ H₂₁F₆ NO.C₂ H₂ O₄.(0.25)H₂ O; C, 53.96; H, 4.62; N, 2.73%.

EXAMPLE 61-(Bis-3,5-trifluoromethylbenzyoxy)-2-(carboxamido)methylamino-2-phenylcyclohexane

The title compound was prepared using an analogous procedure as outlinedin Example 4. ¹ H NMR (360 MHz, DMSO) δ 1.30-1.44 (2H, m), 1.48-1.58(1H, m), 1.59-1.64 (2H, m), 1.84-2.06 (2H, m), 2.08-2.16 (2H, m), 2.96,3.12 (2H, ABq, J=15.6 Hz), 4.04-4.14 (1H, m), 4.43, 4.75 (2H, ABq,J=12.6 Hz), 7.30-7.56 (5H, m), 7.90 (2H, s) and 7.98 (1H, s). Theoxalate salt was recrystallized in ethanol/water mp=48°-50° C. Found: C,54.65; H, 5.19; N, 4.88 requires C₂₃ H₂₂ N₂ O₂ F₆.(0.6)C₂ H₂ O₄.(0.25)H₂O; C, 54.53; H, 4.86; N, 5.25%.

EXAMPLE 7 1,5-Bis-(3,5-dimethylbenzyloxy)-2-amino-2-phenylcyclohexane

The title compound was prepared using an analogous procedure as outlinedin Example 1 using 4-(3,5-dimethylbenzyoxy)cyclohexene oxide. ¹ H NMR(360 MHz, DMSO) δ 1.44-1.68 (2H, m), 1.68-2.10 (4H, m), 2.19 (6H, s),2.23 (6H, s), 2.40-2.51 (2H, m), 3.58-3.65 (1H, m), 3.68-3.75 (1H, m),4.10-4.43 (4H, m) and 6.60-7.62 (11H, m). The oxalate salt wasrecrystallized in petroleum ether-ethyl acetate. mp=103°-105° C. Found:C, 69.66; H, 7.45; N, 2.53, requires C₃₀ H₃₇ NO₂.C₂ H₂ O₄.(0.25)H₂ O; C,69.36; H, 7.18; N, 2.52%.

The following examples illustrate pharmaceutical compositions accordingto the invention.

EXAMPLE 8A

Tablets containing 1-25 mg of compound

    ______________________________________                                                       Amount mg                                                      ______________________________________                                        Compound of formula (I)                                                                         1.0        2.0   25.0                                       Microcrystalline cellulose                                                                     20.0       20.0   20.0                                       Modified food corn starch                                                                      20.0       20.0   20.0                                       Lactose          58.5       57.5   34.5                                       Magnesium Stearate                                                                              0.5        0.5    0.5                                       ______________________________________                                    

EXAMPLE 8B

Tablets containing 26-100 mg of compound

    ______________________________________                                                       Amount mg                                                      ______________________________________                                        Compound of formula (I)                                                                        26.0      50.0    100.0                                      Microcrystalline cellulose                                                                     80.0      80.0     80.0                                      Modified food corn starch                                                                      80.0      80.0     80.0                                      Lactose          213.5     189.5   139.5                                      Magnesium Stearate                                                                              0.5       0.5     0.5                                       ______________________________________                                    

The compound of formula (I), cellulose, lactose and a portion of thecorn starch are mixed and granulated with 10% corn starch paste. Theresulting granulation is sieved, dried and blended with the remainder ofthe corn starch and the magnesium stearate. The resulting granulation isthen compressed into tablets containing 1.0 mg, 2.0 mg, 25.0 mg, 26.0mg, 50.0 mg and 100 mg of the active compound per tablet.

EXAMPLE 9

Parenteral injection

    ______________________________________                                                             Amount mg                                                ______________________________________                                        Compound of formula (I)                                                                              1 to 100 mg                                            Citric Acid Monohydrate                                                                              0.75 mg                                                Sodium Phosphate       4.5 mg                                                 Sodium Chloride        9 mg                                                   Water for Injections   to 1 ml                                                ______________________________________                                    

The sodium phosphate, citric acid monohydrate and sodium chloride aredissolved in a portion of the water. The compound of formula (I) isdissolved or suspended in the solution and made up to volume.

EXAMPLE 10

Topical formulation

    ______________________________________                                                             Amount mg                                                ______________________________________                                        Compound of formula (I)                                                                              1-10 g                                                 Emulsifying Wax        30 g                                                   Liquid paraffin        20 g                                                   White Soft Paraffin    to 100 g                                               ______________________________________                                    

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. Thecompound of formula (I) is added and stirring continued until dispersed.The mixture is then cooled until solid.

I claim:
 1. A compound of formula (I), or a salt or prodrug thereof:##STR9## wherein X represents O or S;R¹ represents phenyl optionallysubstituted by 1, 2 or 3 groups selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl,--OR^(a), SR^(a), SOR^(a), SO₂ R^(a), --NR^(a) R^(b), --NR^(a) COR^(b),--NR^(a) CO₂ R^(b), --CO₂ R^(a) or --CONR^(a) R^(b) ; R² representsphenyl optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, halo ortrifluoromethyl; R³ and R⁴ each independently represent H, COR^(a), CO₂R^(a) or C₁₋₆ alkyl optionally substituted by a group selected from (CO₂R^(a), CONR^(a) R^(b), hydroxy, cyano, COR^(a), NR^(a) R^(b), and phenyloptionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, halo ortrifluoromethyl); R⁵ represents H or XCH₂ R⁶ wherein R⁶ representsphenyl optionally substituted by 1, 2 or 3 groups selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, cyano, nitro, trifluoromethyl,trimethylsilyl, --OR^(a), SR^(a), SOR^(a), SO₂ R^(a), --NR^(a) R^(b),--NR^(a) COR^(b), --NR^(a) CO₂ R^(b), --CO₂ R^(a) or --CONR^(a) R^(b)and X is as previously defined; R⁷ and R⁸ each independently represent Hor C₁₋₆ alkyl; and R^(a) and R^(b) each independently represent H, C₁₋₆alkyl, phenyl or trifluoromethylwith the exception of2-amino-2-phenyl-1-benzyloxycyclohexane.
 2. A compound as claimed inclaim 1 wherein R⁷ and R⁸ each represent H.
 3. A compound as claimed inclaim 1 wherein X represents O.
 4. A compound as claimed in claim 1wherein R¹ represents phenyl substituted by one or more methyl ortrifluoromethyl groups.
 5. A compound as claimed in claim 1 wherein R²represents unsubstituted phenyl.
 6. A compound as claimed in claim 1wherein one of R³ and R⁴ represents H and the other of R³ and R⁴represents H or CH₂ CONH₂.
 7. A compound as claimed in claim 1 whereinR⁵ is H.
 8. A pharmaceutical composition comprising a compound asclaimed in claim 1 in association with a pharmaceutically acceptablecarrier.
 9. A process for the preparation of a compound as claimed inclaim 1 which process comprisesreacting a compound of formula (II):##STR10## wherein R¹, R⁵, R⁷, R⁸ and X are as defined for formula (I)and R³⁰ represents an alkyl or a phenyl group, with a reagent of formulaR² --M, where R² is as defined for formula (I) and M represents analkali metal.
 10. A method for the treatment of a physiological disorderassociated with an excess of tachykinins, which method comprisesadministration to a patient in need thereof of a tachykinin-reducingamount of a compound according to claim
 1. 11. A method according toclaim 10 for the treatment of pain or inflammation.
 12. A methodaccording to claim 10 for the treatment of migraine.
 13. A methodaccording to claim 10 for the treatment of arthritis.
 14. A compoundwhich is selectedfrom:1-(3,5-dimethylbenzyloxy)-2-amino-2-phenylcyclohexane;1-(3,5-dimethylbenzyloxy)-2-dimethylamino-2-phenylcyclohexane;1-(3,5-dimethylbenzyloxy)-2-methoxycarbonylmethylamino-2-phenylcyclohexane;1-(3,5-dimethylbenzyloxy)-2-(carboxamido)methylamino-2-phenylcyclohexane;1-(bis-3,5-trifluoromethylbenzyloxy)-2-amino-2-phenylcyclohexane;1-(bis-3,5-trifluoromethylbenzyloxy)-2-(carboxamido)methylamino-2-phenylcyclohexane;1,5-bis-(3,5-dimethylbenzyloxy)-2-amino-2-phenylcyclohexane;and saltsand prodrugs thereof.